DNA Methylation and Histone Acetylation Regulate the Expression of MGMT and Chemosensitivity to Temozolomide in Malignant Melanoma Cell Lines

Overview

Journal Tumour Biol

Publisher Sage Publications

Specialty Oncology

Date 2016 Mar 5

PMID 26943799

Citations 8

Authors

Ya-Ping Chen

Xiao-Yang Hou

Chun-Sheng Yang

Xiao-Xiao Jiang

Ming Yang

Xi-Feng Xu

Shou-Xin Feng

Yan-Qun Liu

Guan Jiang

Affiliations

Soon will be listed here.

Abstract

Malignant melanoma is an aggressive, highly lethal dermatological malignancy. Chemoresistance and rapid metastasis limit the curative effect of multimodal therapies like surgery or chemotherapy. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes adducts from the O6-position of guanine to repair DNA damage. High MGMT expression is associated with resistance to therapy in melanoma. However, it is unknown if MGMT is regulated by DNA methylation or histone acetylation in melanoma. We examined the effects of the DNA methylation inhibitor 5-Aza-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A alone or in combination on MGMT expression and promoter methylation and histone acetylation in A375, MV3, and M14 melanoma cells. This study demonstrates that MGMT expression, CpG island methylation, and histone acetylation vary between melanoma cell lines. Combined treatment with 5-Aza-2'-deoxycytidine and Trichostatin A led to reexpression of MGMT, indicating that DNA methylation and histone deacetylation are associated with silencing of MGMT in melanoma. This study provides information on the role of epigenetic modifications in malignant melanoma that may enable the development of new strategies for treating malignant melanoma.

Citing Articles

DNA methylation variations of DNA damage response correlate survival and local immune status in melanomas.

Wang M, Zhang X, Yang H, Li Y, Chen W, Yin A Immun Inflamm Dis. 2024; 12(9):e1331.

PMID: 39254643 PMC: 11386344. DOI: 10.1002/iid3.1331.

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers.

Gracia-Hernandez M, Munoz Z, Villagra A Cancers (Basel). 2021; 13(24).

PMID: 34944799 PMC: 8699560. DOI: 10.3390/cancers13246180.

MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System.

Teuber-Hanselmann S, Worm K, Macha N, Junker A Int J Mol Sci. 2021; 22(8).

PMID: 33917711 PMC: 8068191. DOI: 10.3390/ijms22083845.

Tanshinone IIA induces apoptosis via inhibition of Wnt/β‑catenin/MGMT signaling in AtT‑20 cells.

Li Z, Huang G, Chen L, Zhang C, Chen B, Li Q Mol Med Rep. 2017; 16(5):5908-5914.

PMID: 28849207 PMC: 5865768. DOI: 10.3892/mmr.2017.7325.

DNA methylation profiles in cancer diagnosis and therapeutics.

Pan Y, Liu G, Zhou F, Su B, Li Y Clin Exp Med. 2017; 18(1):1-14.

PMID: 28752221 DOI: 10.1007/s10238-017-0467-0.

References

Jiang G, Wei Z, Pei D, Xin Y, Liu Y, Zheng J . A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy. Biochem Biophys Res Commun. 2011; 406(3):311-4. DOI: 10.1016/j.bbrc.2011.02.042. View

Ma S, Egyhazi S, Ueno T, Lindholm C, Kreklau E, Stierner U . O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma. Br J Cancer. 2003; 89(8):1517-23. PMC: 2394337. DOI: 10.1038/sj.bjc.6601270. View

Tentori L, Graziani G . Recent approaches to improve the antitumor efficacy of temozolomide. Curr Med Chem. 2009; 16(2):245-57. DOI: 10.2174/092986709787002718. View

Hegi M, Liu L, Herman J, Stupp R, Wick W, Weller M . Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008; 26(25):4189-99. DOI: 10.1200/JCO.2007.11.5964. View

Weinstein D, Leininger J, Hamby C, Safai B . Diagnostic and prognostic biomarkers in melanoma. J Clin Aesthet Dermatol. 2014; 7(6):13-24. PMC: 4086529. View

Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K . A new antifungal antibiotic, trichostatin. J Antibiot (Tokyo). 1976; 29(1):1-6. DOI: 10.7164/antibiotics.29.1. View

Everhard S, Tost J, El Abdalaoui H, Criniere E, Busato F, Marie Y . Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro Oncol. 2009; 11(4):348-56. PMC: 2743215. DOI: 10.1215/15228517-2009-001. View

Shi H, Wei S, Leu Y, Rahmatpanah F, Liu J, Yan P . Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation, and histone acetylation. Cancer Res. 2003; 63(9):2164-71. View

Howard G, Eiges R, Gaudet F, Jaenisch R, Eden A . Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2007; 27(3):404-8. DOI: 10.1038/sj.onc.1210631. View

10.

Wilson A, Power B, Molloy P . DNA hypomethylation and human diseases. Biochim Biophys Acta. 2006; 1775(1):138-62. DOI: 10.1016/j.bbcan.2006.08.007. View

11.

Kokunai Y, Tsuji M, Ito Y, Kurokawa T, Otsuki Y, Moriwaki S . Immunohistochemical analysis of O(6)-methylguanine-DNA methyltransferase in human melanoma in comparison with skin squamous cell carcinoma. Med Mol Morphol. 2013; 47(1):8-13. DOI: 10.1007/s00795-013-0030-3. View

12.

Cesinaro A, Sartori G, Migaldi M, Schirosi L, Pellacani G, COLLINA G . Prognostic significance of MGMT gene promoter methylation in differently treated metastatic melanomas. Pathology. 2012; 44(4):313-7. DOI: 10.1097/PAT.0b013e328353a0ff. View

13.

Meng C, Zhu X, Dai D, Peng G . [Effects of 5-Aza-2'-deoxycytidine and trichostatin A on P16, hMLH1 and MGMT genes and DNA methylation in human gastric cancer cells]. Zhonghua Wei Chang Wai Ke Za Zhi. 2009; 12(5):494-7. View

14.

Sun M, Song C, Huang H, Frankenberger C, Sankarasharma D, Gomes S . HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci U S A. 2013; 110(24):9920-5. PMC: 3683728. DOI: 10.1073/pnas.1305172110. View

15.

Friedman H, Kerby T, Calvert H . Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000; 6(7):2585-97. View

16.

Egyhazi S, Margison G, Hansson J, Ringborg U . Immunohistochemical examination of the expression of O6-methylguanine-DNA methyltransferase in human melanoma metastases. Eur J Cancer. 1997; 33(1):129-34. DOI: 10.1016/s0959-8049(96)00342-5. View

17.

Soejima H, Zhao W, Mukai T . Epigenetic silencing of the MGMT gene in cancer. Biochem Cell Biol. 2005; 83(4):429-37. DOI: 10.1139/o05-140. View

18.

Mason E, Hornick J . Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis. Mod Pathol. 2013; 26(11):1492-7. DOI: 10.1038/modpathol.2013.86. View

19.

Shah N, Lin B, Sibenaller Z, Ryken T, Lee H, Yoon J . Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM. PLoS One. 2011; 6(1):e16146. PMC: 3017549. DOI: 10.1371/journal.pone.0016146. View

20.

Wolffe A, Matzke M . Epigenetics: regulation through repression. Science. 1999; 286(5439):481-6. DOI: 10.1126/science.286.5439.481. View